4,5--VPA-diol (inactive metabolite)
Figure 14.3 • Metabolic pathways of valproic acid.
analogs, a-fluoro-4-ene-VPA and a-fluoro-VPA, were not found to have any liver toxicity.41 These toxic or reactive metabolites are normally detoxified as a cysteine conjugate via the GSH/glutathione transferase metabolic pathway.41 Alternatively, the 4-epoxy-VPA can also be deactivated by epoxy hydrolase to form the corresponding inactive VPA-4, 5-diol (Fig. 14.3). It should be pointed out that these toxic metabolites may also react with the sulfhydryl group or other nucleophiles on the cellular proteins, thereby forming covalently bonded haptens. These drug-modified proteins then elicit and become the target of an immune response, thereby producing the observed idiosyncratic allergic reactions in clinically susceptible patients.
Valrocemide (valproyl glycinamide, VLR) and DP-VPA (SPD-421) are two novel VPA analogs currently in phase II clinical trials42,43 (Fig. 14.4). The anticonvulsant properties of VLR were found to be a result of the parent molecule and not because of its metabolic biotransformation to VPA or glycine (i.e., itself an inhibitory neurotrans-mitter in the brain). The major in vivo inactive metabolite is valproyl glycine, which is formed via the normal metabolic inactivation of peptide drugs.42 SPD-421, on the other hand, is a phosphatidylcholine derivative of VPA. The phospholipid part of the molecule significantly increases its lipid solubility and facilitates its transport into the brain. Furthermore, SPD-421 was found to be minimally metabolized in the liver with most of the drug renally eliminated. However, upon entry into the brain, SPD-421 is specifically cleaved by the enzyme, phosplipase A2 (PLA2), at the site of seizure to release VPA (there is evidence that the activity of PLA2 is significantly increased in neurons associated with epileptiform activity prior to seizure attack).43 Thus, unlike VPA, both of these drugs are said to have low drug-interaction potentials.
Phenytoin (Dilantin, Kapseals, Phenytek) and Fosphenytoin (Cerebyx)
Phenytoin, 5,5-diphenylhydantoin (Dilantin), is a prime example of an effective anticonvulsant acting through its action at the VGSC.18 Phenytoin is structurally very similar to phenobarbital but lacks the dependence liability (see the discussion of barbiturate-type anxiolytic hypnotic-sedative drugs under "CNS Depressants" in this
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